Adenosine modulates the immune system and inhibits inflammation via reduction of cytokine biosynthesis and neutrophil functions. Drugs able to prevent adenosine catabolism could represent an innovative strategy to treat inflammatory bowel disorders. In this study, the effects of 4-amino-2- (2-hydroxy-1-decyl)pyrazole[3,4-d]pyrimidine (APP, novel adenosine deaminase inhibitor), erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA, standard adenosine deaminase inhibitor) and dexamethasone were tested in rats with colitis induced by 2,4-dinitrobenzenesulfonic acid (DNBS). DNBS-treated animals received APP (5, 15 or 45 µmol/kg), EHNA (10, 30 or 90 µmol/kg) or dexamethasone (0.25 µmol/kg), intraperitoneally for 7 days, starting 1 day before colitis induction. DNBS caused bowel inflammation associated with decrease in food intake and body weight. Animals treated with APP or EHNA, but not dexamethasone, displayed greater food intake and weight gain than inflamed rats. Colitis induced increment in spleen weight, which was counteracted by all test drugs. DNBS administration was followed by macroscopic and microscopic inflammatory colonic alterations, which were ameliorated by APP, EHNA or dexamethasone. In DNBS-treated rats, colonic myeloperoxidase, malondialdehyde and tumour necrosis factor-alfa?(TNF- alfa) levels as well as plasma TNF-alfa?and interleukin-6 were increased. All test drugs lowered these phlogistic indexes. Inflamed colonic tissues displayed an increment of inducible nitric oxide synthase mRNA, which was unaffected by APP or EHNA, but reduced by dexamethasone. Cyclooxygenase-2 expression was unaffected by DNBS or test drugs. These findings indicate that: 1) inhibition of adenosine deaminase results in a significant attenuation of intestinal inflammation; 2) the novel compound APP is more effective than EHNA in reducing systemic and intestinal inflammatory alterations.
Inhibition of adenosine deaminase attenuates inflammation in experimental colitis
Vassalle C;
2007
Abstract
Adenosine modulates the immune system and inhibits inflammation via reduction of cytokine biosynthesis and neutrophil functions. Drugs able to prevent adenosine catabolism could represent an innovative strategy to treat inflammatory bowel disorders. In this study, the effects of 4-amino-2- (2-hydroxy-1-decyl)pyrazole[3,4-d]pyrimidine (APP, novel adenosine deaminase inhibitor), erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA, standard adenosine deaminase inhibitor) and dexamethasone were tested in rats with colitis induced by 2,4-dinitrobenzenesulfonic acid (DNBS). DNBS-treated animals received APP (5, 15 or 45 µmol/kg), EHNA (10, 30 or 90 µmol/kg) or dexamethasone (0.25 µmol/kg), intraperitoneally for 7 days, starting 1 day before colitis induction. DNBS caused bowel inflammation associated with decrease in food intake and body weight. Animals treated with APP or EHNA, but not dexamethasone, displayed greater food intake and weight gain than inflamed rats. Colitis induced increment in spleen weight, which was counteracted by all test drugs. DNBS administration was followed by macroscopic and microscopic inflammatory colonic alterations, which were ameliorated by APP, EHNA or dexamethasone. In DNBS-treated rats, colonic myeloperoxidase, malondialdehyde and tumour necrosis factor-alfa?(TNF- alfa) levels as well as plasma TNF-alfa?and interleukin-6 were increased. All test drugs lowered these phlogistic indexes. Inflamed colonic tissues displayed an increment of inducible nitric oxide synthase mRNA, which was unaffected by APP or EHNA, but reduced by dexamethasone. Cyclooxygenase-2 expression was unaffected by DNBS or test drugs. These findings indicate that: 1) inhibition of adenosine deaminase results in a significant attenuation of intestinal inflammation; 2) the novel compound APP is more effective than EHNA in reducing systemic and intestinal inflammatory alterations.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
